Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter and local hormone, is formed by the hydroxylation and decarboxylation of tryptophan. The greatest concentration is found in the enterochromaffin cells of the gastrointestinal tract, the remainder being predominantly present in platelets and in the Central Nervous System (CNS). 5-HT is implicated in a vast array of physiological and pathophysiological pathways. In the periphery, it contracts a number of smooth muscles and induces endothelium-dependent vasodilation. In the CNS, it is believed to be involved in a wide range of functions, including the control of appetite, mood, anxiety, hallucinations, sleep, vomiting and pain perception.
Neurons that secrete 5-HT are termed serotonergic. The function of 5-HT is exerted upon its interaction with specific (serotonergic) neurons. Seven types of 5-HT receptors have been identified: 5-HT1 (with subtypes 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E and 5-HT1F), 5-HT2 (with subtypes 5-HT2A, 5-HT2B and 5-HT2C), 5-HT3, 5-HT4, 5-HT5 (with subtypes 5-HT5A and 5-HT5B), 5-HT6 and 5-HT7. Most of these receptors are coupled to G-proteins that affect the activities of either adenylate cyclase or phospholipase Cγ.
The human 5-HT6 receptors are positively coupled to adenylyl cyclase. They are distributed throughout the limbic, striatal and cortical regions of the brain and show a high affinity to antipsychotics.
The modulation of the 5-HT6 receptor by suitable substances is expected to improve certain disorders including cognitive dysfunctions, such as a deficit in memory, cognition and learning, in particular associated with Alzheimer's disease, age-related cognitive decline and mild cognitive impairment, attention deficit disorder/hyperactivity syndrome, personality disorders, such as schizophrenia, in particular cognitive deficits related with schizophrenia, affective disorders such as depression, anxiety and obsessive compulsive disorders, motion or motor disorders such as Parkinson's disease and epilepsy, migraine, sleep disorders (including disturbances of the Circadian rhythm), feeding disorders, such as anorexia and bulimia, certain gastrointestinal disorders such as Irritable Bowel Syndrome, diseases associated with neurodegeneration, such as stroke, spinal or head trauma and head injuries, such as hydrocephalus, addiction diseases and obesity (see e.g. A. Meneses, Drug News Perspect 14(7) (2001) pp. 396-400 and literature cited therein; J. Pharmacol. Sci. Vol. 101 (Suppl. 1), 2006, p. 124. Modulators of the 5HT6-receptor such as PRX-07034 (Epix Pharmaceuticals) have been found in preclinical and clinical studies to be particular useful in the treatment of cognitive dysfunctions, in particular associated with Alzheimer's disease or schizophrenia or in the treatment of obesity (see e.g. http://www.epixpharma.com/products/prx-07034.asp).
Compounds with a structural similarity to the compounds of the present invention have been described in WO 03/080580, WO 2005/113539, WO 2007/039219, WO 2007/039238 and WO 2009/019286.
However, there is still an ongoing need for providing compounds having high affinity for the 5-HT6 receptor and which advantageously also show high selectivity to this receptor.
Besides the binding affinity for the 5-HT6 receptor, further properties may be advantageous for the treatment and/or prophylaxis of 5-HT6-dependent disorders, such as, for example:
1.) a selectivity for the 5-HT6 receptor compared with the 5-HT1A receptor, i.e. the quotient of the binding affinity for the 5-HT1A receptor (Ki(5-HT1A) (determined in the unit “nanomolar (nM)”) and the binding affinity for the 5-HT6 receptor (Ki(5-HT6)) (determined in the unit “nanomolar (nM)”). A larger quotient Ki(5-HT1A)/Ki(5-HT6) means a greater 5-HT6 selectivity;
2.) a selectivity for the 5-HT6 receptor compared with the 5-HT2A receptor, i.e. the quotient of the binding affinity for the 5-HT2A receptor (Ki(5-HT2A) (determined in the unit “nanomolar (nM)”) and the binding affinity for the 5-HT6 receptor (Ki(5-HT6)) (determined in the unit “nanomolar (nM)”). A larger quotient Ki(5-HT2A)/Ki(5-HT6) means a greater 5-HT6 selectivity.
3.) a selectivity for the 5-HT6 receptor compared with the 5-HT2B receptor, i.e. the quotient of the binding affinity for the 5-HT2B receptor (Ki(5-HT2B) (determined in the unit “nanomolar (nM)”) and the binding affinity for the 5-HT6 receptor (Ki(5-HT6)) (determined in the unit “nanomolar (nM)”). A larger quotient Ki(5-HT2B)/Ki(5-HT6) means a greater 5-HT6 selectivity.
4.) a low affinity to adrenergic receptors, such as α1-adrenergic receptor, histamine receptors, such as H1-receptor, and dopaminergic receptors, such as D2-receptor, in order to avoid or reduce considerable side effects associated with modulation of these receptors, such as postural hypotension, reflex tachycardia, potentiation of the antihypertensive effect of prazosin, terazosin, doxazosin and labetalol or dizziness associated to the blockade of the α1-adrenergic receptor, weight gain, sedation, drowsiness or potentiation of central depressant drugs associated to the blockade of the H1-receptor, or extrapyramidal movement disorder, such as dystonia, parkinsonism, akathisia, tardive dyskinesia or rabbit syndrome, or endocrine effects, such as prolactin elevation (galactorrhea, gynecomastia, menstruyl changes, sexual dysfunction in males), associated to the blockade of the D2-receptor.
5.) the metabolic stability, for example determined from the half-lives, measured in vitro, in liver microsomes from various species (e.g. rat or human);
6.) no or only low inhibition of cytochrome P450 (CYP) enzymes: cytochrome P450 (CYP) is the name for a superfamily of heme proteins having enzymatic activity (oxidase). They are also particularly important for the degradation (metabolism) of foreign substances such as drugs or xenobiotics in mammalian organisms. The principal representatives of the types and subtypes of CYP in the human body are: CYP 1A2, CYP 2C9, CYP 2D6 and CYP 3A4. If CYP 3A4 inhibitors (e.g. grapefruit juice, cimetidine, erythromycin) are used at the same time as medicinal substances which are degraded by this enzyme system and thus compete for the same binding site on the enzyme, the degradation thereof may be slowed down and thus effects and side effects of the administered medicinal substance may be undesirably enhanced;
7.) a suitable solubility in water (in mg/ml);
8.) suitable pharmacokinetics (time course of the concentration of the compound of the invention in plasma or in tissue, for example brain). The pharmacokinetics can be described by the following parameters: half-life (in h), volume of distribution (in 1·kg−1), plasma clearance (in l·h−1·kg−1), AUC (area under the curve, area under the concentration-time curve, in ng·h·l−1), oral bioavailability (the dose-normalized ratio of AUC after oral administration and AUC after intravenous administration), the so-called brain-plasma ratio (the ratio of AUC in brain tissue and AUC in plasma);
9.) no or only low blockade of the hERG channel: compounds which block the hERG channel may cause a prolongation of the QT interval and thus lead to serious disturbances of cardiac rhythm (for example so-called “torsade de pointes”). The potential of compounds to block the hERG channel can be determined by means of the displacement assay with radiolabelled dofetilide which is described in the literature (G. J. Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187-199). A smaller IC50 in this dofetilide assay means a greater probability of potent hERG blockade. Moreover, the blockade of the hERG channel can be measured by electrophysiological experiments on cells which have been transfected with the hERG channel, by so-called whole-cell patch clamping, as shown in the below assay (G. J. Diaz et al., Journal of Pharmacological and Toxicological Methods, 50 (2004), 187-199). The higher the Ki values in the below assay (determined in the unit “micromolar (μM)”), the lower the probability of potent hERG blockade.
One object of the present invention was to provide compounds which have a high affinity for the 5-HT6 receptor. A further object of the present invention was to provide compounds which selectively bind to the 5-HT6 receptor [especially as mentioned above under 1.), 2.), 3.) and/or 4.)]. In addition, the compounds of the invention should have one or more of the aforementioned advantages mentioned under 5.) to 9.) and specifically under 5.) (metabolic stability).
The present invention provides compounds which have an affinity for the 5-HT6 receptor, thus allowing the treatment of disorders related to or affected by the 5-HT6 receptor.